Modified viruses have been used to deliver genetic material to cells, both for research/development purposes and for clinical purposes. Some of the most successful gene transfer systems (‘vectors’) are based on retroviruses, and more recently, on lentiviruses, a subfamily of retrovirideae. Retroviral vectors have the advantages of being able to efficiently infect a broad range of cell types, and of being able to integrate the genetic material they carry (e.g. exogenous therapeutic genes) into the genome of the target cell (e.g. cells of the human patient). However, retroviral vectors can only infect dividing cells, and this limits their use.
Lentiviral vectors have a number of advantages over retroviral vectors including the ability to infect both dividing and non-dividing cells.
However, for both retroviral and lentiviral vectors there are concerns that the genetic homology between the packaging constructs and the constructs comprising the packageable vectors and/or other viral sequences, including sequences present in the cells in which the retroviral vectors are produced, could lead to recombination events that could generate a dangerous replicating virus.
These recombination events are particularly prone to occur in the cell line in which the vector is produced. This is because, in order for the cell line to produce the vector, it must contain certain viral sequences which express the proteins and other factors necessary to package the vector into a virus-like particle that then can infect cells, reverse transcribe RNA and integrate the proviral DNA into the host cell genome. Recombination between the vector and these ‘helper’ sequences may in theory produce a dangerous replicating virus.
Testing of lentiviral vector biosafety in appropriate animal models is a major concern associated with the use of lentiviral vectors in clinical trials. As HIV-1 only causes AIDS in humans, there is presently no animal model to test the safety of HIV-1 based vectors.